Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula: ##STR1## or pharmaceutically acceptable addition salts thereof wherein: Y represents oxygen or sulfur; Z is nitrogen or CH; 
     R 1 , R 2  and R 3  independently represent organic or inorganic substituents; 
     R 4  and R 4  &#39; independently represent hydrogen, alkyl or form a ring with the atom to which they are attached; 
     R 5  represents hydrogen, alkyl, alkoxy, or alkylthio, and R 6  represents hydrogen or alkyl; or R 5  and R 6  form a ring together with the atoms to which they are attached; and 
     R 7 , R 8 , R 9 , R 10  and R 11  independently represent hydrogen or alkyl, 
     which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

CROSS-REFERENCE

This application claims benefit of Provisional application No.60/076,043, filed Feb. 26, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to substituted 2-(4-benzylpiperazin-1-yl) and2-(1-benzylpiperidin-4-yl)ethanones and to pharmaceutical compositionscontaining such compounds. It also relates to the use of such compoundsin the treatment or prevention of psychotic disorders such asschizophrenia and other central nervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has been identified(Nature, 347: 146 (Sokoloff et al., 1990)). Its unique localization inlimbic brain areas and its differential recognition of variousantipsychotics suggest that the D₄ receptor may play a major role in theetiology of schizophrenia. Selective D₄ antagonists are consideredeffective antipsychotics free from the neurological side effectsdisplayed by conventional neuroleptics.

Various 4-benzylpiperazines have been described. See, for example, Arch.Med. Res., 25: 435-440 (Terron et al., 1994) and Toxicol. Appl.Pharmacol., 7: 257-267 (Schmidt and Martin, 1965).

SUMMARY OF THE INVENTION

The invention provides novel compounds which interact with dopaminereceptor subtypes. Accordingly, in a broad aspect, the inventionprovides compounds of Formula I: ##STR2## wherein: Y represents oxygenor sulfur;

Z is nitrogen or CH;

R₁, R₂ and R₃ independently represent hydrogen, halogen, hydroxy, loweralkoxy, C₁ -C₆ alkyl, trifluoromethyl or trifluoromethoxy;

R₄ and R₄ ' independently represent hydrogen or C₁ -C₆ alkyl; or

R₄ and R₄ ' together with the atom to which they are attached form aring having from 3-7 members;

R₅ represents hydrogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, or C₁ -C₆alkylthio;

R₆ is hydrogen or C₁ -C₆ alkyl; or

R₅ and R₆ together represent C₁ -C₅ alkylene, C₁ -C₄ alkyleneoxy, C₁ -C₄alkylenethio where the oxygen or sulfur atoms are immediately adjacentthe phenyl ring, and together with the atoms to which they are attachedform a ring having from 5-9 members; and

R₇, R₈, R₉, R₁₀, and R₁₁ independently represent hydrogen or C₁ -C₆alkyl.

Dopamine D₄ receptors are concentrated in the limbic system (Science,265: 1034 (Taubes, 1994)) which controls cognition and emotion.Therefore, compounds that interact with these receptors are useful inthe treatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders include those involving memory impairment or attention deficitdisorders.

Compounds of the present invention demonstrate high affinity andselectivity in binding to the D₄ receptor subtype. These compounds aretherefore useful in treatment of a variety of neuropsychologicaldisorders, such as, for example, schizophrenia, psychotic depression andmania. Other dopamine-mediated diseases such as Parkinsonism and tardivedyskinesias can also be treated directly or indirectly by modulation ofD₄ receptors.

Compounds of this invention are also useful in the treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₄receptors since they exist selectively in areas known to control emotionand cognitive functions.

Thus, in another aspect, the invention provides methods for treatmentand/or prevention of neuropsychochological or affective disordersincluding, for example, schizophrenia, mania, dementia, depression,anxiety, compulsive behavior, substance abuse, memory impairment,cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonismand dystonia, and motion disorders related to the use of neurolepticagents. In addition, the compounds of the invention are useful intreatment of depression, memory-impairment or Alzheimer's disease.Further, the compounds of the present invention are useful for thetreatment of other disorders that respond to dopaminergic blockade,e.g., substance abuse and obsessive compulsive disorder. These compoundsare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents.

In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

In a yet further aspect, the invention provides intermediates useful forpreparing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the invention encompasses substituted2-(4-benzyl)-piperazinyl- and piperidinyl-1-ethanones of Formula I.Preferred compounds of Formula I are those where R₂ and R₃ are not bothhydrogen simultaneously. Other preferred compounds of Formula I arethose where R₇, R₈, R₉, and R₁₀ are hydrogen. In the compounds of theinvention, R₁₁ is preferably hydrogen, methyl or ethyl, most preferablyhydrogen.

As noted, the invention encompasses compounds where R₅ and R₆ togetherrepresent C₁ -C₅ alkylene, C₁ -C₄ alkyleneoxy, and C₁ -C₄ alkylenethio.In these compounds, the oxygen or sulfur atoms are immediately adjacentthe phenyl ring carrying the R₅ group. In such cases, R₅ and R₆ togetherwith the atoms to which they are attached form a ring having from 5-9members. Examples of such rings include the following: ##STR3##

Preferred among these bicyclic ring systems are compounds where n is 0or an integer of 1 or 2.

In these compounds, R₄ and R₄ ' independently represent hydrogen or C₁-C₆ alkyl, or R₄ and R₄ ' together with the atom to which they areattached form a ring having from 3-7 members. Representative resultingspiro ring systems include the following: ##STR4##

Compounds in which R₅ and R₆ together with the atoms to which they areattached form a ring having from 5-9 members as discussed above arerepresented by Formula II: ##STR5## wherein X represents oxygen, orsulfur, or CH; Y is oxygen or sulfur;

Z is nitrogen or CH;

n is zero or an integer of from 1-4;

R₁, R₂ and R₃ independently represent hydrogen, halogen, hydroxy, loweralkoxy, C₁ -C₆ alkyl, trifluoromethyl or trifluoromethoxy;

R₄ and R₄ ' independently represent hydrogen or C₁ -C₆ alkyl; or

R₄ and R₄ ' together with the atom to which they are attached form aring having from 3-7 members;

R₇, R₈, R₉, R₁₀, and R₁₁ independently represent hydrogen or C₁ -C₆alkyl.

Preferred compounds of Formula II are those where R₂ and R₃ are notsimultaneously hydrogen. In preferred compounds of Formula II, R₄ and R₄' are independently hydrogen or C₁ -C₄ alkyl. In other preferredcompounds of Formula II, n is 0 or 1, and more preferably 0.

A preferred group of compounds of Formula II are those where Y isoxygen, X is CH₂ and Z is CH. Such compounds are depicted by FormulaIIa: ##STR6## wherein n, R₁, R₂, R₃, R₄, R₄ ' R₇, R₈, R₉, R₁₀, and R₁₁are as defined above for Formula II.

In the compounds of Formula IIa, R₁₁ is preferably hydrogen, methyl orethyl. In preferred compounds of Formula IIa, R₁ is hydrogen or halogen,and R₂ and R₃ are independently selected from hydrogen, C₁ -C₆ alkyl,and halogen. More preferred such compounds of Formula IIa are thosewhere R₁₁ is hydrogen or methyl, R₁ is hydrogen or halogen, and not bothof R₂ and R₃ are hydrogen simultaneously. Particularly preferredcompounds of Formula IIa are those where R₁₁ is hydrogen or methyl, R₂is hydrogen, R₃ is methyl, methoxy, chloro, or fluoro, R₄ and R₄ ' areindependently hydrogen or lower alkyl, most preferably C₁ -C₂ alkyl, andR₁ is hydrogen or halogen.

Another preferred group of compounds of Formula II are those where Z isnitrogen and X is CH₂. Such compounds are generally represented byFormula IIb: ##STR7## wherein n, Y, R₁, R₂, R₃, R₄, R₄ ' R₇, R₈, R₉,R₁₀, and R₁₁ are as defined above for Formula II.

In such compounds, R₁₁ is preferably hydrogen, methyl or ethyl. Further,in such preferred compounds, Y is oxygen, R₁ is hydrogen or halogen, andR₂ and R₃ are independently selected from hydrogen, C₁ -C₆ alkyl, andhalogen. More preferred compounds of Formula IIb are those where R₁₁ ishydrogen or methyl, Y is oxygen, R₁ is hydrogen or halogen, and not bothof R₂ and R₃ are hydrogen simultaneously. Particularly preferredcompounds of Formula IIb where R₁₁ is hydrogen or methyl, Y is oxygen,R₂ is hydrogen, R₃ is methyl, methoxy, chloro, or fluoro, R₄ and R₄ 'are independently hydrogen or lower alkyl, most preferably C₁ -C₂ alkyl,and R₁ is hydrogen or halogen.

Compounds of Formula I where R₅ is hydrogen or lower alkyl and R₆ are ishydrogen are represented by Formula III: ##STR8## wherein Y, Z, R₁, R₂,R₃, R₄, R₄ ' R₅, R₇, R₈, R₉, R₁₀, and R₁₁ are as defined above forFormula I. In the compounds of Formula III, R₂ and R₃ are preferably notboth hydrogen simultaneously.

A preferred group of compounds of Formula III, hereinafter Formula IIIa,are those where Y is oxygen, Z is nitrogen, R₁ is hydrogen or halogen,and R₂ and R₃ are independently selected from hydrogen, C₁ -C₆ alkyl,and halogen. Still more preferred compounds of Formula IIIa are thosewhere not both of R₂ and R₃ are hydrogen simultaneously. Other preferredcompounds of Formula IIIa are those where R₂ is hydrogen, R₃ is methyl,chloro, or fluoro, and one or both of R₄ and R₄ ' are lower alkyl, mostpreferably C₁ -C₂ alkyl, and R₁ is hydrogen or halogen. Particularlypreferred compounds of Formula IIIa are those where R₂ is hydrogen andR₃ is a methyl, chloro, or fluoro group in the 4 position on the phenylring. Other particularly preferred compounds of Formula IIIa are thosewhere the phenyl substituted with R₂ and R₃ is 2-alkoxy-5-halophenyl.Representative of such particularly preferred compounds are those wherethe phenyl carrying R₂ and R₃ is 2-(C₁ -C₂)alkoxy-5-fluoro or5-chlorophenyl.

Another preferred group of compounds of Formula III, hereinafter FormulaIIIb, are those where Y is oxygen, Z is CH, R₁ is hydrogen or halogen,and R₂ and R₃ are independently selected from hydrogen, C₁ -C₆ alkyl,and halogen. Still more preferred compounds of Formula IIIb are thosewhere not both of R₂ and R₃ are hydrogen simultaneously. Other preferredcompounds of Formula IIIb are those where R₂ is hydrogen, R₃ is methyl,chloro, or fluoro, and one or both of R₄ and R₄ ' are lower alkyl, mostpreferably C₁ -C₂ alkyl, and R₁ is hydrogen or halogen. Particularlypreferred compounds of Formula IIIb are those where R₂ is hydrogen andR₃ is a methyl, chloro, or fluoro group in the 4 position on the phenylring. Other particularly preferred compounds of Formula IIIb are thosewhere the phenyl substituted with R₂ and R₃ is 2-alkoxy-5-halophenyl.Representative of such particularly preferred compounds are those wherethe phenyl carrying R₂ and R₃ is 2-(C₁ -C₂)alkoxy-5-fluoro or-5-chlorophenyl. ##STR9##

The substituents on Formulae IIIa and IIIb are as defined above forFormula III.

Another preferred group of compounds of the invention is encompassed byFormula IV, i.e., where R₅ and R₆ together form a ring and R₄ and R₄ 'also together form a ring: ##STR10## wherein X, n, Y, Z, R₁, R₂, R₃, R₇,R₈, R₉, R₁₀, and R₁₁ are as defined above for Formula I, and m is zeroor an integer of from 1-4. Preferably, R₂ and R₃ are not both hydrogensimultaneously in the compounds of Formula IV.

Preferred compounds of Formula IV are those where X is CH₂, n is 0, R₄and R₄ ' form a five-membered carbocyclic ring with the atom to whichthey are attached (i.e., m is 2), and R₁₁ is hydrogen. Where Z inFormula IV is CH, the resulting compounds having m=2 are designatedFormula IVa. Where Z in Formula IV is nitrogen, the resulting compoundshaving m=2 are designated Formula IVb. ##STR11##

In preferred compounds of each of Formulae IVa and IVb, X is CH₂, Y isoxygen, and n is 0. More preferred compounds are those where X is CH₂, Yis oxygen, and n is 0, R₁ is hydrogen or halogen, and R₂ and R₃ areindependently selected from hydrogen, C₁ -C₆ alkyl, and halogen. Stillmore preferred compounds of these formulae are those where X is CH₂, Yis oxygen, and n is 0 and not both of R₂ and R₃ are hydrogensimultaneously. Other preferred compounds of Formulae IVa and IVb arethose where Z is CH, Y is oxygen, R₂ is hydrogen, and R₃ is methyl,fluoro or chloro. Particularly preferred compounds of these formulae arethose where X is CH₂, Y is oxygen, and n is 0, R₂ is hydrogen and R₃ isa methyl, chloro or fluoro group in the 4 position on the phenyl ring.Other particularly preferred compounds of these formulas are those wherethe phenyl substituted with R₂ and R₃ is 2-alkoxy-5-halophenyl.

Also encompassed within the scope of the invention are intermediatesuseful in preparing compounds of the invention. Thus, the inventionprovides compounds of Formula VII-a: ##STR12## wherein X, n, Y, and R₁are as defined above for Formula I, m is zero or an integer of from 1-4,and L is a leaving group, such as, for example, halogen, methanesulfonyl, or toluenesulfonyl. A preferred group of compounds of FormulaVII-a are those where Y is oxygen, X is oxygen or, more preferably,methylene, m is 2, and R₁ is hydrogen or halogen.

Another group of intermediates is encompassed by Formula VII-b:##STR13## wherein Y, R₁ R₄, R₄ ' R₅ are as defined above for Formula I,and L is a leaving group.

A preferred group of compounds of Formula VII-b are those where Y isoxygen or, more preferably, methylene, and R₁ is hydrogen or halogen.Other preferred compounds of Formula VII-b are those where one or bothof R₄ and R₄ ' are lower alkyl, most preferably C₁ -C₂ alkyl, and R₁ ishydrogen or halogen.

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC--(CH₂)n--ACOOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By "alkyl" or "lower alkyl" in the present invention is meant C₁ -C₆alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbonatoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl.

By "alkoxy" or "lower alkoxy" in the present invention is meant C₁ -C₆alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term "halogen" in the present invention is meant fluorine,bromine, chlorine, and iodine.

Representative compounds of the invention are shown below in Table 1.

                  TABLE 1                                                         ______________________________________                                         ##STR14##                                                                    Compound 1a                                                                    ##STR15##                                                                    Compound 2a                                                                    ##STR16##                                                                    Compound 3a                                                                    ##STR17##                                                                    Compound 4a                                                                    ##STR18##                                                                    Compound 5a                                                                    ##STR19##                                                                    Compound 6a                                                                    ##STR20##                                                                    Compound 7                                                                     ##STR21##                                                                    Compound 10                                                                   ______________________________________                                    

The compounds of the invention are useful in the treatment ofneuropsychological disorders; the pharmaceutical utility of compounds ofthis invention is indicated by the assays for dopamine receptor subtypeaffinity described below in the Examples. The interaction of thesubstituted 2-(4-Phenylmethyl)-piperazino-1-ethanones of the inventionwith dopamine receptor subtypes results in the pharmacologicalactivities of these compounds.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Representative illustrations of methods suitable for the preparation ofcompounds of the present invention are shown in the following Schemes.Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention. For example, in certainsituations, protection of reactive moieties such as amino groups, willbe required.

A 2-(4-benzylpiperazin-1-yl-1-ethanone compound of Formula I may beprepared according to the reactions shown in Scheme 1. ##STR22## whereinR₁, R₂, R₃, R₄, R₄ ', R₅, R₆, and Y are as defined above for Formula I.

As shown in Scheme 1, an aniline of general structure V having anappropriate secondary amino group is condensed with chloroacetylchloride or an appropriate derivative thereof (VI). The resultingintermediate VII in turn is reacted with a piperazine derivative ofgeneral structure VII to provide a 2-(4-benzylpiperazin-1-yl)-1-ethanonederivative of Formula I. The piperazine derivatives VIII are generallycommercially available but may also be prepared using methods describedin the literature.

The 2-(4-benzylpiperazin-1-yl)-1-ethanones of the invention may beprepared according to the reactions shown below in Scheme 2. ##STR23##wherein the substituents carry the same definitions as set forth abovefor Formula I.

As shown in Scheme 2, an ester of pyridine-4-acetic acid (XI) may bereduced with hydrogen gas in the presence of a catalyst, e.g., platinum,to provide piperidine aminoester derivative XII. Aminoester XII may becondensed with an appropriate benzylic alkylating agent containing aleaving group W, wherein W may be a halogen or a sulfonate ester or thelike, to provide an N-benzylpiperidine of general structure XIII. Theester group of XIII may be saponified in base to provide an amino acidof general structure XIV which is subsequently condensed with asecondary amine to provide the desired compounds of Formula I wherein Zis a methine carbon (Z=CH).

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present inventions, as demonstrated by the followingexamples. In some cases, protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral, the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE 1

Preparation of Starting Materials and Intermediates

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

A representative example of a method for preparing the ethanoneintermediates of the invention is set forth below. ##STR24##

A quantity of 2,3-dihydro-1H-1-indole (also known as indoline, 2.1 g,17.6 mmol) is dissolved in toluene (60 ml). To the solution of the aminein toluene is added acetyl chloride (2.0 g, 17.6 mmol) dissolved in1,2-dichloroethane (20 ml). The reaction mixture turns brown uponaddition of the acid chloride. The reaction is allowed to proceed atroom temperature, with stirring, for about 3 hr, after which thereaction mixture is diluted with ethyl acetate and washed with 50:50(v/v) water:saturated NaCl solution (2 times). The organic phase isdried over anhydrous MgSO₄ and concentrate to yield2-Chloro-1-(2,3-dihydro-1H-1-indolyl)-1-ethanone (may also be named2-chloro-1-indolinylethan-1-one) in 85% yield (2.92 g, 15 mmol) as alight brown solid.

EXAMPLE 2 ##STR25##

To a solution of (4-chlorobenzyl)-piperazine (1.5 g, 7.2 mmol) inacetonitrile (100 ml) is added2-Chloro-1-(2,3-dihydro-1H-1-indolyl)-1-ethanone (1.4 g, 7.16 mmol) andK₂ CO₃ (12 g, 87 mmol). The reaction mixture is allowed to proceed atroom temperature for about 6 hr. The reaction mixture is then filteredand concentrated and the residue resuspended in ethyl acetate andextracted with HCl (3M). The aqueous phase is basified with NaOH (10M)and then back-extracted with more ethyl acetate. The final ethyl acetatephase is washed with brine, dried over anhydrous MgSO₄ and concentrated.Thus the desired2-(4-(4-chlorobenzyl)-piperazino-1-(2,3-dihydro-1H-1-indolyl)-1-ethanone(alternatively named2-(4-(4-chlorobenzyl)piperazinyl)-1-indolinylethan-1-one) is obtained asa light pink solid (1.3 g, 3.5 mmol) in 50% yield. Mp: 139.5-140° C. ¹ HNMR (400 MHz, CDCl₃) d 8.23 ppm (d., 1 H, 8.8 Hz), 7.26 ppm (m., 4 H),7.24 ppm (m., 2 H), 7.01 ppm (t., 1 H, 7.2 Hz), 4.16 ppm (t., 2 H, 8.4Hz), 3.48 ppm (s, 2 H), 3.25 ppm (s., 2 H), 3.19 ppm (br. t., 2 H, 8.4Hz), 2.64 ppm (br s, 4 H), 2.51 ppm (br. s., 4 H) and MS (CI) M⁺ 369.

The HBr salt of the title compound (Compound 19) is prepared from amethanolic solution (using 48% aqueous HBr), and recrystallized fromethanol/acetone to yield a white solid, mp: 258-260° C.

EXAMPLE 3

The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2:

(a)2-(4-(4-chlorobenzyl)piperazino-1-(2-methyl-2,3-dihydro-1H-1-indolyl)-1-ethanone(compound 3) (dihydrobromide salt: Compound 3a).

(b)2-(4-(4-chlorobenzyl)piperazino-1-(1,2,3,4-tetrahydro-1-quinolinyl)-1-ethanone(Compound 4) (dihydrobromide salt: Compound 4a).

(c)2-(4-(4-chlorobenzyl)piperazino-1-(3,4-dihydro-2H-benzo[b]1,4-oxazin-4-yl)-1-ethanone(Compound 5) (dihydrobromide salt: Compound 5a).

(d)2-(4-(4-chlorobenzyl)-piperazino-1-(3,4-dihydro-2H-benzo[b]1,4-thiazin-4-yl)-1-ethanone(Compound 6) (hydrobromide salt: Compound 6a).

(e)1-(2,2-dimethylindolinyl)-2-(4-(4-chlorobenzyl)-piperazinyl)ethan-1-one(Compound 7).

(f)1-(2,2-dimethylindolinyl)-2-(4-(4-methylbenzyl)-piperazinyl)ethan-1-one(Compound 8).

(g) 1-(2-methylindolinyl)-2-(4-(4-methylbenzyl)-piperazinyl)ethan-1-one(Compound 9).

(h)2-(4-[4-chlorobenzyl]piperazinyl)-1-spiro[cyclopentane-2,2'-indolin-1yl]ethanone(Compound 10).

(i) 2-(4-(4-chlorobenzyl)piperazinyl)-1-(4-fluoroindolinyl)ethan-1-one(Compound 11).

(j)1-(5-chloro-2,2-dimethylindolinyl)-2-(4-(4-chlorobenzyl)piperazinyl)ethan-1-one(Compound 12).

(k)2-(4-(5-chloro-2-methoxybenzyl)piperazinyl)-1-(2-methylindolinyl)ethan-1-one(Compound 13).

(1) 2-(4-(4-chlorobenzyl)piperazinyl)-1-(2-methylindolinyl)ethan-1-one(both resolved enantiomers) ##STR26##

(m) 1-indolinyl-2-(4-(4-methylbenzyl)piperazinyl)propan-1-one (Compound15).

(n)1-(2,2-dimethylindolinyl)-2-(4-(4-fluorobenzyl)piperazinyl)ethan-1-one(Compound 16).

(o) 2-(4-(4-chlorobenzyl)piperazinyl)-1-(7-methylindolinyl)ethan-1-one(Compound 17).

(p) 1-(6-chloroindolinyl)-2-(4-(4-chlorobenzyl)piperazinyl)ethan-1-one(Compound 18).

(q) N-butyl-2-(4-(4-chlorobenzyl)piperazinyl)-N-phenylethanamide(Compound 2) (dihydrobromide salt: Compound 2a).

EXAMPLE 4 ##STR27##

Ethyl-4-pyridylacetate (5 g) is dissolved in ethanol (30 mL), treatedwith platinum oxide catalyst (30 mg) and hydrogenated on a Parrapparatus for 4 hr. The catalyst is filtered off and theethyl-4-piperidinylacetate is isolated by removal of the solvent undervacuum. This material is then dissolved in acetonitrile (50 mL) andtreated with 4-chlorobenzyl chloride (4.9 g) and sodium carbonate (10g). The resulting mixture is heated in methanol (30 mL) and treated witha solution of lithium hydroxide (2 g) in water (10 mL). The mixture isallowed to stand overnight. Addition of 47.6 mL of 1 N HCI solutionfollowed by concentration and extraction of the residue with chloroformprovides the desired 1-(4-chlorobenzyl)-4-piperidylacetic acid. Aportion of this material (1 g) is dissolved in methylene chloride andtreated with 1,1'-carbonyldiimidazole (0.65 g) and allowed to standovernight. This solution is then treated with 2-methylindoline (0.5 g).After 2 h the resulting mixture is washed 3 times with water dried andconcentrated. Purification by column chromatography on silica gelprovides 1.2 g of the desired2-(1-[4-chlorobenzyl]piperidin-4-yl)-1-(2-methylindolin-1-yl)-1-ethanone(Compound 1). The dihydrochloride salt is subsequently prepared(Compound 1a).

EXAMPLE 5

Assay for D₂ and D₄ Receptor Binding Activity

The pharmaceutical utility of compounds of this invention is indicatedby the assays for dopamine receptor subtype affinity described below.

Pellets of CHO cells containing human D₂ or D₄ receptors cloned fromc-DNA are used for assays (Tallman, J. F. et. al., J. Pharm. Exp. Ther.,1997, 282, 1011). The cloned membranes are homogenized in 100 volumes(wt/vol) of 0.05M Tris-HCl buffer at 4° C. and pH 7.4 containing 120 mMNaCl, 1 mM EDTA and 5 mM MgCl₂. The samples were centrifuged at 48,000×gthen re-suspended and re-homogenized. The final tissue sample is keptfrozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05MTris-HCl buffer containing 120 mM NaCl prior to use.

Incubations were carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³ H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Non-specific binding is defined as that binding found in the presence of1 mM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding. Binding characteristics for examples ofcompounds encompassed within Formula I for the D₂ and D₄ receptorsubtypes are shown in Table 2 for rat striatal homogenates.

                  TABLE 2                                                         ______________________________________                                        Compound No..sup.1                                                                           D.sub.4 K.sub.I (nM)                                                                    D.sub.2 K.sub.I (nM)                                 ______________________________________                                        1              7            92                                                2              154       ND                                                   3              0.7          74                                                4              47        10,000                                               5              429         2610                                               6              14.2      10,000                                               ______________________________________                                         .sup.1 Compound numbers relate to the compounds shown in Table 1.        

The binding constants of compounds of Formula I for the D₄ receptor,expressed in nM, generally range from about 0.1 nanomolar (nM) to about500 nanomolar (nM). Preferred compounds have binding constraints of fromabout 0.1 to 100 nM. Preferred compounds typically have bindingconstants for the D₂ receptor at least about 10-15 times that of the D₄binding constant. Thus, the compounds of the invention are generally atleast about 10 time more selective for the D₄ receptor than the D₂receptor. Preferably, these compounds are at least 20, and morepreferably at least 25-50, times more selective for the D₄ receptor thanthe D₂ receptor. Most preferably, the compounds of Formula I are atleast 100 times more selective for the D₄ receptor than the D₂ receptor.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR28## orpharmaceutically acceptable addition salts thereof wherein: Y representsoxygen or sulfur;R₁, R₂ and R₃ independently represent hydrogen,halogen, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, trifluoromethyl ortrifluoromethoxy; R₄ and R₄ ' independently represent hydrogen or C₁ -C₆alkyl; or R₄ and R₄ ' together with the atom to which they are attachedform a ring having from 3-7 members; R₅ represents hydrogen, C₁ -C₆alkyl, C₁ -C₆ alkoxy, or C₁ -C₆ alkylthio; R₆ is hydrogen or C₁ -C₆alkyl; or R₅ and R₆ together represent C₁ -C₅ alkylene, C₁ -C₅alkyleneoxy, C₁ -C₅ alkylenethio where the oxygen or sulfur atoms areimmediately adjacent the phenyl ring, and together with the atoms towhich they are attached form a ring having from 5-9 members; and R₇, R₈,R₉, R₁₀, and R₁₁ independently represent hydrogen or C₁ -C₆ alkyl,provided that not both R₄ and R₄ ' are hydrogen when R₅ and R₆ do nottogether represent C₁ -C₅ alkylene, C₁ -C₅ alkyleneoxy, or C₁ -C₅alkylenethio.
 2. A compound according to claim 1, wherein only one of R₂and R₃ is hydrogen.
 3. A compound according to claim 1, having theformula: ##STR29## wherein X represents oxygen, sulfur, or CH; Y isoxygen or sulfur;Z is nitrogen; n is zero or an integer of from 1-4; R₁,R₂ and R₃ independently represent hydrogen, halogen, hydroxy, C₁ -C₆alkoxy, C₁ -C₆ alkyl, trifluoromethyl or trifluoromethoxy; R₄ and R₄ 'independently represent hydrogen or C₁ -C₆ alkyl; or R₄ and R₄ 'together with the atom to which they are attached form a ring havingfrom 3-7 members; R₇, R₈, R₉, R₁₀ and R₁₁ independently representhydrogen or C₁ -C₆ alkyl.
 4. A compound according to claim 1, having theformula: ##STR30## wherein n is an integer of from 1-4; Y is oxygen; andR₁, R₂, R₃, R₄, R₄ ' R₇, R₈, R₉, R₁₀, and R₁₁ are as defined above inclaim
 1. 5. A compound according to claim 1, having the formula:##STR31## wherein Z is nitrogen;R₄ and R₄ ' together with the atom towhich they are attached form a ring having from 3-7 members; R₅represents hydrogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, or C₁ -C₆ alkylthio;and Y, R₁, R₂, R₃, R₇, R₈, R₉, R₁₀, and R₁₁ are as defined above inclaim
 1. 6. A compound according to claim 1, having the formula:##STR32## wherein n is an integer of from 1-4; and Y, X, R₁, R₂, R₃, R₇,R₈, R₉, R₁₀, and R₁₁ are as defined above in claim
 1. 7. A compoundaccording to claim 6, wherein Y is oxygen, R₁ is hydrogen or halogen,and R₂ and R₃ are independently selected from hydrogen, C₁ -C₆ alkyl,and halogen.
 8. A compound according to claim 7, wherein not both of R₂and R₃ are hydrogen simultaneously.
 9. A compound according to claim 7,wherein R₂ is hydrogen and R₃ is methyl, chloro or fluoro.
 10. Acompound according to claim 9, wherein R₃ is a methyl, chloro or fluorogroup in the 4 position on the phenyl ring.
 11. A compound according toclaim 10, wherein n is
 0. 12. A compound according to claim 5, wherein Yis oxygen, R₁ is hydrogen or halogen, and R₂ and R₃ are independentlyselected from hydrogen, C₁ -C₆ alkyl, and halogen.
 13. A compoundaccording to claim 1, which is2-(4-(4-chlorobenzyl)piperazinyl)-1-indolinylethan-1-one.
 14. A compoundaccording to claim 1, which is2-(4-(4-chlorobenzyl)piperazino-1-(2-methyl-2,3-dihydro-1H-1-indolyl)-1-ethanone.15. A compound according to claim 1, which is2-(4-(4-chlorobenzyl)piperazino-1-(1,2,3,4-tetrahydro-1-quinolinyl)-1-ethanone.16. A compound according to claim 1, which is2-(4-(4-chlorobenzyl)piperazino-1-(3,4-dihydro-2H-benzo[b]1,4-oxazin-4-yl)-1-ethanone.17. A compound according to claim 1, which is2-(4-(4-chlorobenzyl)-piperazino-1-(3,4-dihydro-2H-benzo[b]1,4-thiazin-4-yl)-1-ethanone.18. A compound according to claim 1, which is1-(2,2-dimethylindolinyl)-2-(4-(4-chlorobenzyl)piperazinyl)ethan-1-one.19. A compound according to claim 1, which is1-(2,2-dimethylindolinyl)-2-(4-(4-methylbenzyl)-piperazinyl)ethan-1-one.20. A compound according to claim 1, which is1-(2-methylindolininy-2-(4-(4-methylbenzyl)-piperazinyl)ethan-1-one. 21.A compound according to claim 1, which is2-(4-(4-chlorobenzyl)piperazinyl)-1-spiro[cyclopentane-2,2'-indolin-1-yl]ethanone.
 22. A compound according toclaim 1, which is2-(4-(4-chlorobenzyl)piperazinyl)-1-(4-fluoroindolinyl)ethan-1-one. 23.A compound according to claim 1, which is1-(5-chloro-2,2-dimethylindolinyl)-2-(4-(4-chlorobenzyl) piperazinyl)ethan-1-one.
 24. A compound according to claim 1, which is2-(4-(5-chloro-2-methoxybenzyl)piperazinyl)-1-(2-methylindolinyl)ethan-1-one.
 25. A compound according to claim 1, which is ##STR33## 26.A compound according to claim 1, which is
 27. A compound according toclaim 1, which is1-indolinyl-2-(4-(4-methylbenzyl)piperazinyl)propan-1-one.
 28. Acompound according to claim 1, which is1-(2,2-dimethylindolinyl)-2-(4-(4-fluorobenzyl)piperazinyl)ethan-1-one.29. A compound according to claim 1, which is2-(4-(4-chlorobenzyl)piperazinyl)-1-(7-methylindolinyl)ethan-1-one. 30.A compound according to claim 1, which is1-(6-chloroindolinyl)-2-(4-(4-chlorobenzyl)piperazinyl)ethan-1-one. 31.A compound according to claim 1, which is1-(4-(4-chlorobenzyl)-piperazinyl)-2-indolinylethan-1-one.
 32. Acompound according to claim 1, which isN-butyl-2-(4-(4-chlorobenzyl)piperazinyl)-N-phenylethanamide.